Nucleic acids related to fusion proteins

摘要

The present invention concerns a family of nucleic acids, polypeptides and cloning vectors which direct expression of fusion proteins that can mimic aggregated IgG (AIG) and immune complex function with respect to their interactions with FcγR and which allow for the inclusion and targeting of a second protein domain to cells expressing FcγR. This was accomplished by expressing multiple linear copies of the hinge and CH2 domains (HCH2) of human IgG1 fused to the framework region of human IgG1. Convenient restriction sites allow for the facile introduction of additional amino-terminal domains. Methods for treating patients using fusion proteins are also disclosed. The HCH2 polymers described here represent a new strategy in the design of recombinant proteins for the therapeutic targeting of FcγR in autoimmune disorders.

主权项

1. A nucleic acid encoding a polypeptide consisting of a dimer of a first amino acid chain and a second amino acid chain, which can be the same or different, and where each amino acid chain comprises:
a first region comprising a protein or portion thereof; a second region comprising two to six copies of at least a portion of an HCH2 region of a first mammalian IgG, where the HCH2 region comprises a hinge of the first mammalian IgG and a CH2 of the first mammalian IgG; and a third region comprising a hinge of a second mammalian IgG, a CH2 of the second mammalian IgG, and a CH3 of the second mammalian IgG; wherein (1) one or more cysteines of the hinge of the HCH2 region of one or both amino acid chains is mutated to an amino acid selected from the group consisting of serine, alanine, glycine, and threonine, (2) the first mammalian IgG and the second mammalian IgG are from the same mammal, and (3) the polypeptide targets to cells expressing a low affinity FcγR or binds to a low affinity FcγR.